PB1849: TRIAL IN PROGRESS: PHASE IB/II STUDY OF SIREMADLIN IN COMBINATION WITH VENETOCLAX + AZACITIDINE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA (AML) WHO ARE INELIGIBLE FOR INTENSIVE CHEMOTHERAPY
Authors: N. G. Daver, A. H. Wei, E. M. Stein, D. J. DeAngelo, D. Pathak, Y. Xu, S. Grzesiak, A. Venditti
Journal: HemaSphere (2022)

Background: Treatment options for patients with AML who are not candidates for intensive chemotherapy (IC) are limited. The addition of venetoclax to hypomethylating agents demonstrated improved remission rates and survival; however, relapse rates are high, and most patients remain measurable residual disease (MRD) positive (DiNardo CD, N Engl J Med, 2020). Murine double minute-2 (MDM2) is a key negative regulator of tumor protein 53 (p53). Inhibition of the p53-MDM2 interaction results in up-regulation of the tumor-suppressive effect of p53. Siremadlin is a selective inhibitor of the p53-MDM2 interaction. Siremadlin + venetoclax has shown durable antitumor responses in p53-wild-type AML patient-derived xenograft models (Wang Y, Cancer Res, 2019). Findings from a first-in-human Phase I study with siremadlin demonstrated a tolerable safety profile and preliminary antitumor activity in patients with AML (Stein EM, Clin Cancer Res, 2021; NCT02143635). Preliminary results from the ongoing Phase Ib study exploring siremadlin in combination with venetoclax showed promising antileukemic activity in patients with relapsed/refractory AML (Wei AH, ASH 2021; NCT03940352). Aims: Here we describe the study design of a Phase Ib/II study to assess the safety and efficacy of the novel combination of siremadlin + venetoclax + azacitidine in patients with AML who are unfit for IC (NCT05155709). Methods: The study will enroll approximately 55 adult patients with AML who are unfit for IC due to older age (≥75 y) or presence of comorbidities (cardiac or pulmonary, Eastern Cooperative Oncology Group performance status of 2 or 3). Patients with prior myelodysplastic syndrome, myelofibrosis, essential thrombocythemia, polycythemia, or therapy-related AML may also be eligible. Patients with TP53 mutation or del17p are excluded. Two subpopulations will be evaluated in 2 arms: patients with prior suboptimal response (no complete remission [CR], CR with partial/incomplete hematologic recovery [CRh/CRi], or morphologic leukemia-free state) after 2-4 cycles of first-line venetoclax + azacitidine (Arm 1) and patients with newly diagnosed AML with high-risk clinical features that confer a low likelihood of response to venetoclax + hypomethylating agents (adverse genetic risk stratification per European Leukemia Network, 2017; Arm 2). The study will consist of a safety run-in (Part 1) and expansion phase (Part 2; Figure). The safety run-in will evaluate safety across 2 siremadlin dose levels (20 or 30 mg) from Day (D)1 to D5 in each 28-d treatment cycle in combination with venetoclax and azacitidine. In Arm 1, pts will continue receiving their venetoclax and azacitidine doses that were evaluated as tolerable prior to study enrollment. In Arm 2, venetoclax will be ramped up over 3 days to a target daily dose of 400 mg and azacitidine (75 mg/m2) will be administered from D1–D7 or from D1–D5, and D8 and D9). Upon confirmation of the recommended dose for expansion (RDE, determined for each arm separately), enrollment for the expansion phase (Part 2) will open; patients will be treated with siremadlin at the RDE in combination with venetoclax + azacitidine. The primary endpoints are incidence of dose-limiting toxicities (Arm 1 and Arm 2 separately) and CR rate (Arm 1 only). Secondary endpoints include safety and tolerability; CR rate (Arm 2 only); CR/CRh and CR/CRi rates; duration of CR, CRi, and CRh; overall survival; early mortality; MRD; and pharmacokinetics. Results: None, trial in progress. Image:Summary/Conclusion: None, trial in progress.